Unit 1 General Pharmacology (As per PCI syllabus)

It covers basic concepts of pharmacology. It is only for educational purpose.

1. UNIT :1
General Pharmacology
Presented by: Prof.MirzaAnwar Baig
Anjuman-I-Islam's KalsekarTechnical Campus
School of Pharmacy,NewPavel,NaviMumbai,Maharashtra
1
1Presented by: Prof.Mirza Anwar
Baig

2. Contents:
A.Introduction to Pharmacology-
Definition, historical landmarks and scope of pharmacology,
nature and source of drugs, essential drugs concept and routes
of drug administration.
Agonists, antagonists( competitive and non competitive),
spare receptors, addiction, tolerance, dependence,
tachyphylaxis, idiosyncrasy, allergy.
B.Pharmacokinetics-
Membrane transport, absorption, distribution, metabolism and
excretion of drugs.
Enzyme induction, enzyme inhibition, kinetics of elimination
2Presented by: Prof.Mirza Anwar
Baig

3. At the end of topic you should be able to....
1.Compare advantage and disadvantages of routes of drug
administration.
2. Explain the essential characteristics of drug for proper
absorption & excretion.
3. Summarize the role of distribution and metabolism
in drug actions.
3Presented by: Prof.Mirza Anwar
Baig

4. 1.Pharmacology:
•Science of drugs (Greek:Pharmacon--drug; logos-discourse in).
•Deals with interaction of exogenously administered chemical
molecules (drugs) with living systems.
The two main divisions of pharmacology are:
•Pharmacodynamics: knowledge about drugs, but most importantly -
What the drug does to the body.
•Pharmacokinetics(Greek: Kinesis-movement):-What the body
does to the drug.
4Presented by: Prof.Mirza Anwar
Baig

5. 2. Drug (French: Drogue -a dry herb)
"Drug is any substance or product that is used or is intended to be
used to modify or explore physiological systems or pathological
states for the benefit of the recipient."
3. Pharmacotherapeutics:
•Itistheapplicationofpharmacologicalinformationtogetherwith
knowledgeofthediseaseforitsprevention,mitigationorcure.
•Selectionofthemostappropriatedrug,dosageanddurationof
treatmenttakingintoaccountthespecificfeaturesofapatientare
apartofpharmacotherapeutics.
5Presented by: Prof.Mirza Anwar
Baig

6. 4.Clinical pharmacology:
Scientific study of drugs in man.
Pharmacodynamic and pharmacokinetic investigation in
healthy volunteers and in patients.
Evaluation of efficacy and safety of drugs
Comparative trialswith other forms of treatment;
Surveillanceof patterns of drug use, adverse effects etc.
5. Chemotherapy:
Treatment of systemic infection/malignancy
Specific drugs that have selective toxicity for the infecting
organism malignant cell with no/minimal effects on the host cells
6Presented by: Prof.Mirza Anwar
Baig

7. 6.Toxicology:
It is the study of poisonous effectof drugs and other
chemicals (household, environmental pollutant,
industrial, agricultural, homicidal) with emphasis on
detection, prevention and treatment of poisonings.
It also includes the study of adverse effectsof drugs,
since the same substance can be a drug or a poison,
depending on the dose.
7Presented by: Prof.Mirza Anwar
Baig

8. DRUG NOMENCLATURE
Threecategoriesofnames:
(a)Chemicalname:
Itdescribesthesubstancechemically,e.g.1-(lsopropylamino)-
3-(1-naphthyloxy)propan-2-olforpropranolol.
Thisiscumbersomeandnotsuitableforuseinprescribing.
Acodename,e.g.RO15-1788(laternamedflumazenil)may
beassignedbyhemanufacturerforconvenienceand
simplicitybeforeanapprovednameiscoined.
b)Brandname–
Originaldrugwhichisdefendedbypatentandmaybeproduced
duringpatenttermonlybythispharmaceuticalfirm
c)Genericname–
Whentermofpatentisdiscontinuedthedrugmaybeproducedby
differentpharmaceuticalcompaniesundernewproduct(trade)names
butatthebasisoforiginalactivesubstance(similarquantity,routeof
administrationetc.)
8Presented by: Prof.Mirza Anwar
Baig

9. ESSENTIAL DRUGS (MEDICINES) CONCEPT
The WHO has defined Essential Drugs (medicines) as "those that
satisfy the priority healthcare needs of the population.
They are selectedwith due regard to public health relevance,
evidence on efficacy and safety, and comparative cost effective.
Essential medicines are intended to be availablewithin the context
of functioning health systems at all timesand in adequate amounts,
in appropriate dosage forms, with assured quality and adequate
information, and at a affordable price.
For optimum utilization of resources, governments (especially in
developing countries) should concentrate on well
tested,cheaper,safe and efficacious drugs by identifying them as
Essential medicines.
9Presented by: Prof.Mirza Anwar
Baig

10. WHO criteria for the selection of an essential
medicine.
a) Adequate dataon its efficacy and safety should be available.
b) Available in a formin which quality, including bioavailability, and stability on
storage can be assured.
c) Its choice should depend upon pattern of prevalent diseases;availability of
facilities and trained personnel; financial resources; genetic, demographic and
enviromental factors.
d) In case of two or more similar medicines, choice should be made on the basis of
their relative efficacy,safety, quality, price and availability,by comparative
pharmacokinetic properties and local facilities for manufacture and storage.
f) Most essential medicines should be single compounds.
Fixed ratio combination productsshould be included only when dosage of each
ingradient meets the requirements of a defined population group, and when the
combination has a proven advantage in therapeutic effect, safety, adherence or in
decreasing the emergence of drug resistance.
10Presented by: Prof.Mirza Anwar
Baig

11. (g) Selection of essential medicines should be a continuous process
which should take into account the changing prioritiesfor public
health action, epidemiological conditionsas well as availability of
better medicines/ formulations and progress in pharmacological
knowledge.
(h) Recently, it has been emphasized to select essential medicines
based on rationally developed treatment guidelines.
First Model List of Essential Drugs along with their dosage forms
and strengths in 1977 by WHO which could be adopted after
suitable modifications according to local needs.
India produced its National Essential Drugs List in 1996and has
revised it in 2003 with the title "National List of Essential Medicines".
This includes 354 medicineswhich are considered to be adequate
to meet the priority healthcare needs of the general population of the
country.
Adoption of the essential medicines listfor procurement and supply
of medicines, especially in the public sector healthcare system, has
resulted in improved availability of medicines, cost saving and more
rational use of drugs.
11Presented by: Prof.Mirza Anwar
Baig

12. Orphan Drugs
•These are drugs or biological productsfor diagnosis/treatment/
prevention of a rare disease or condition, or a more common
disease (endemic only in resource poor countries) for which there is
no reasonable expectation that the cost of developing and marketing
it will be recoveredfrom the sales of that drug.
•The list includes:
Sodium nitrite, fomepizole, liposomal amphotericin 8, ancrod,
rifabutin, succimer, somatropin, digoxin immune Fab (digoxin
antibody), liothyronine (T3) and many more.
•Though these drugs may be life saving for some patients, they are
commercially difficult to obtain.
•Governments in developed countries offer tax benefitsand other
incentives to pharmaceutical companies for developing and
marketing orphan drugs (e.g. Orphan Drug Act in USA).
12Presented by: Prof.Mirza Anwar
Baig

13. Route of drug adminsteration
Definition:
A route of administration is the pathby which a
drug, fluid, poison or other substance is brought
into contact with the body.
13Presented by: Prof.Mirza Anwar
Baig

14. Classification
Routes of administration can broadly be divided into:
1. Topical:
Drugs are applied topically to the skin or mucous membranes, mainly for
local action.
2. Oral:
used for systemic (non-local) effect, substance is given via the digestive
tract.
3. Parenteral:
A drug administered parenterally is one injected via a hollow needle into
the body at various sites and to varying depth.
4. Rectal:Drugs given through the rectum by suppositories or enema.
5. Inhalation:The lungs provide an excellent surface for absorption when
the drug is delivered in gaseous, aerosol or ultrafine solid particle form
14Presented by: Prof.Mirza Anwar
Baig

15. ROUTES OF DRUG ADMINISTRATION
Mostly common considerations are:
1. Physical and chemical properties of the drug
-Solid/liquid/ gas
–Solubility and stability
–PH and irritancy
2. Site of desired action-localized and aprochable
3. Rate and extent of absorption of the drug from different
routes.
4. Effect of digestive juices and first pass metabolismof the
drug.
5. Rapiditywith which the response is desired (eg.routine
treatment or emergency).
6. Accuracy of dosage required (i.v. and inhalation).
7. Condition of the patient(unconscious, vomiting) etc.
15Presented by: Prof.Mirza Anwar
Baig

16. Local route
•Theseroutescanonlybeusedforlocalizedlesionsat
accessiblesitesandfordrugswhosesystemicabsorption
fromthesesitesisminimalorabsent.
•Thus,highconcentrationsareattainedatthedesiredsite
withoutexposingtherestofthebody.
•Systemicsideeffectsortoxicityareconsequentlyabsentor
minimal.
•Thesamecanserveassystemicrouteofadministration,e.g.
glyceryltrinitrate(GTN)appliedontheskinasointmentor
transdermalpatch.
16Presented by: Prof.Mirza Anwar
Baig

17. A.Topical route
This refers to external application of the drug to the surface
for localized action.
It is often more convenient as well as encouraging to the
patient.
Drugs can be efficiently delivered to the localized lesionson
skin, oropharyngeal/nasal mucosa, eyes, ear canal, anal
canal or vagina.
The dosage forms are lotion, ointment, cream,powder, paints,
drops, spray, lozengens, suppositories or pesseries.
Nonabsorbable drugs given orally (sucralfate,
vancomycin), inhalation of drugs for action on bronchi
(salbutamol, cromolyn sodium) and irrigating solutions/jellys
(povidone iodine,lidocaine) applied to urethra
17Presented by: Prof.Mirza Anwar
Baig

18. 1-Topical route:
I Skin
A-Dermal–cream,ointment (local action)
B-Transdermal-absorption of drug through skin (i.e systemic action)
I. stable blood levels(controlled drug delivery system)
II. No first pass metabolism
III. Drug must be potent or patch becomes too large
II Mucosal membranes
•eye drops (onto the conjunctiva)
•ear drops
•intranasal route (into the nose)
18Presented by: Prof.Mirza Anwar
Baig

19. 2-Oral route:
-By swallowing.
-It is intended for systemic effects resulting
from drug absorption through the various
epithelia and mucosa of the
gastrointestinal tract.
19Presented by: Prof.Mirza Anwar
Baig

20. Advantages:
1-Convenient-portable, no pain, easy to take.
2-Cheap-noneedtosterilize,compact,multi-dosebottles,
automatedmachinesproducetabletsinlargequantities.
3-Variety-tablets, capsules, suspensions, mixtures .
Disadvantages:
1-Sometimes inefficient -low solubility drugs may suffer poor
availability e.g. Griseofulvin
2-First-pass effect -drugs absorbed orally are transported to the
general circulation via the liver. Thus drugs which are extensively
metabolized will be metabolized in the liver during absorption. e.g.
propranolol
20Presented by: Prof.Mirza Anwar
Baig

21. First pass effect:
First pass effect
21Presented by: Prof.Mirza Anwar
Baig

22. 1.The first pass effect is the term used for the hepatic metabolismof a
pharmacological agent when it is absorbed from the gut and
delivered to the liver via the portal circulation.
2.Thegreaterthefirstpasseffect,thelowerthebioavailabilityofthe
drug(therateandextentofthedrugreachingsystemiccirculation).
3.Food and G-I motility can affect drug absorption.Often patient
instructions include a direction to take with food or take on an empty
stomach.
4. Absorption is slower with food(milk and milk products) for
tetracyclines and penicillins, etc. However, for propranolol
bioavailability is higher after food, and for griseofulvin absorption is
higher after a fatty meal.
First pass effect (Cont.):
22Presented by: Prof.Mirza Anwar
Baig

23. 5. Sometimes may have adverse reactions–e.g.
Antibiotics may kill normal gut flora and allow
overgrowth of fungal varieties. Thus, antifungal
agent may be included with an antibiotic.
6. Not suitable for unconscious patient -Patient
must be able to swallow solid dosage forms.
Liquids may be given by tube.
7.May cause irritation to gastric mucosa, nausea
and vomiting.
8.Effect too slow for emergencies.
23Presented by: Prof.Mirza Anwar
Baig

24. 3-Buccal/Sublingual route:
•Some drugs are taken as smaller tablets which are
held in the mouth (buccal tablet)or under the
tongue (sublingual tablet).
•Buccal tablets are often harder tablets [4 hour
disintegration time],designed to dissolve slowly.
•E.g Nitroglycerin, as a softer sublingual tablet [2
mindisintegration time],may be used for the rapid
relief of angina.
24Presented by: Prof.Mirza Anwar
Baig

25. Advantages
1-Avoid hepatic first pass-The liver is by-passed thus
there is no loss of drug by first pass effect for buccal
administration. Bioavailability is higher.
2-Rapid absorption-Because of the good blood supply
to the area, absorption is usually quite rapid.
3-Drug stability-pH in mouth relatively neutral (Except.
stomach -acidic). Thus a drug may be more stable.
3-Buccal/Sublingual route (Cont.)
25Presented by: Prof.Mirza Anwar
Baig

26. Disadvantages
1-Holding the dose in the mouth is
inconvenient.
2-Small doses only can be accommodated
easily.
3-Buccal/Sublingual route (Cont.)
26Presented by: Prof.Mirza Anwar
Baig

27. 4-Parenteral route:
27Presented by: Prof.Mirza Anwar
Baig

28. A-Intravascular(IV, IA):
-placing a drug directly into blood stream.
-Maybe-Intravenous(intoavein)or-intraarterial(intoanartery).
Advantages
1-precise,accurateandimmediateonsetofaction,100%
bioavailability.
Disadvantages
1-risk of embolism.
2-high concentrations attained rapidly leading to greater risk of
adverse effects.
4-Parenteral route (Cont.)
28Presented by: Prof.Mirza Anwar
Baig

29. 4-Parenteral route (Cont)
B-Intramuscular :(into the skeletal muscle).
Advantages
1-suitable for injection of drug in aqueous solution (rapid
action) and drug in suspension or emulsion (sustained
release).
Disadvantages
1-Pain at injection sites for certain drugs.
29Presented by: Prof.Mirza Anwar
Baig

30. C-Subcutaneous(under the skin), e.g. insulin.
D-Intradermal, (into the skin itself) is used for skin testing some
allergens.
E-Intrathecal(into the spinal canal) is most commonly used for
spinal anesthesia .
F-Intraperitoneal, (infusion or injection into the peritoneum)
e.g. peritoneal dialysis in case of renal insuffeciency.
4-Parenteral route (Cont)
30Presented by: Prof.Mirza Anwar
Baig

31. 5-Rectal route:
Most commonly by suppository or enema.
Advantages
1-By-pass liver-Some of the veins draining the rectum lead
directly to the general circulation, thus by-passing the liver.
Reduced first-pass effect.
2-Useful-This route may be most useful for patients unable
to take drugs orally (unconscious patients) or with younger
children.
-if patient is nauseous or vomiting
31Presented by: Prof.Mirza Anwar
Baig

32. Disadvantages:
1-Erratic absorption-Absorption is often incomplete
and erratic.
2-Notwellaccepted.
5-Rectal route (Cont.)
32Presented by: Prof.Mirza Anwar
Baig

33. 6-Inhalation route:
-Used for gaseous and volatile agents and aerosols.
-Solids and liquids are excluded if larger than 20 micron.
-Smaller than 0.5 micron , they aren't retained.
Advantages
A-Large surface area
B-thin membranes separate alveoli from circulation
C-high blood flow
-As result of that a rapid onset of actiondue to rapid access
to circulation.
33Presented by: Prof.Mirza Anwar
Baig

34. Disadvantages
1-Most addictive route of administration because it hits the brain
so quickly.
2-Difficulties in regulating the exact amount of dosage.
3-Sometimes patient having difficulties in giving themselves a
drug by inhaler.
6-Inhalation route (Cont.)
34Presented by: Prof.Mirza Anwar
Baig

35. Comparisons:
35Presented by: Prof.Mirza Anwar
Baig

36. Comparisons:
36Presented by: Prof.Mirza Anwar
Baig

37. Pharmacokinetics
Pharmacokinetics refers to what the
body does to a drug & phar-
macodynamics describes what the
drug does to the body.
•Four pharmacokinetic properties determine
the onset, intensity,and the duration of drug
action
•Absorption:
•Distribution:
•Metabolism:
•Elimination:
Using knowledge of pharmacokinetic
parameters, clinicians can design
optimal drug regimens, including the
route of administration, the dose,the
frequency, and the durationof
treatment.
37Presented by: Prof.Mirza Anwar
Baig

38. Drug absorption:
38Presented by: Prof.Mirza Anwar
Baig

39. B.Factors influencing absorption:
1.Effect of pH on drug absorption:
2. Blood flow to the absorption site:
3. Total surface area available for absorption:
4. Contact time at the absorption surface:
5. Expression of P-glycoprotein:
39Presented by: Prof.Mirza Anwar
Baig

40. 1.Effect of pH on drug absorption:
5. Expression of P-glycoprotein:
40Presented by: Prof.Mirza Anwar
Baig

41. Bioavailability
•Bioavailability is the rate and extent to
which an administered drug reaches
the systemic circulation.
•For example,if 100 mg of a drug is
administered orally and 70 mg is
absorbed unchanged, the bio-
availability is 0.7 or 70%.
•Determining bioavailability is
important for calculating drug dosages
for nonintravenous routes of
administration.
Determination of bioavailability:
41Presented by: Prof.Mirza Anwar
Baig

42. 2.Factors that influence bioavailability:
a.First-pass hepatic
metabolism:
b.Solubility of the drug:
c.Chemical instability:
d.Nature of the drug
formulation:
42Presented by: Prof.Mirza Anwar
Baig

43. a. First-pass hepatic metabolism :
What is FPHM:
When a drug is absorbed from the GI tract, it enters the portal circulation
before entering the systemic circulation.
Ifthedrugisrapidlymetabolizedintheliverorgutwallduringthisinitial
passage,theamountofunchangeddrugenteringthesystemic
circulationisdecreased.Thisisreferredtoasfirst-passhepatic
metabolism.
First-passmetabolismbytheintestineorliverlimitstheefficacyofmany
oralmedications.
Forexample:
Morethan90%ofnitroglycerinisclearedduring
first-passmetabolism.Hence,itisprimarilyadministered
viathesublingualortransdermalroute.
Drugswithhighfirst-passmetabolismshouldbegivenindoses
sufficienttoensurethatenoughactivedrugreachesthedesiredsiteof
action.
43Presented by: Prof.Mirza Anwar
Baig

44. Examples:
a. Nitroglycerin pacth b. First pass effect
44Presented by: Prof.Mirza Anwar
Baig

45. b.Solubility of the drug:
•Very hydrophilic drugsare poorly absorbed because of their inability
to cross lipid-rich cell mem-branes.
•Paradoxically, drugs that are extremely lipophilicare
also poorly absorbed, because they are totally insoluble in
aqueous body fluidsand, therefore, cannot gain access to the
surface of cells.
•For a drug to be readily absorbed, it must be largely lipophilic, yet
have some solubility in aqueous solutions.
•This is one reason why many drugs are either weak acids or
weak bases.
c.Chemical instability:
Some drugs, such as penicillin G, are unstable in the pHof the
gastric contents. Others, such as insulin, are destroyed in the
GI tract by degradative enzymes.
45Presented by: Prof.Mirza Anwar
Baig

46. d.Nature of the drug formulation:
Drug absorption may be altered by factors unrelated to the
chemistry of the drug.
For example,
Particle size
Salt form
Crystal polymorphism
Enteric coatings,
Presence of excipients (such as binders and dispersing agents)
can influence the ease of dissolution and,therefore, alter the rate of
absorption.
46Presented by: Prof.Mirza Anwar
Baig

47. D.Bioequivalence
Twodrugformulationsarebioequivalentiftheyshow
comparablebioavailabilityandsimilartimestoachievepeakblood
concentrations.
Clinicaleffectivenessoftendependsonboththemaximum
serumdrugcon-centrationandthetimerequired(afteradministration)to
reachpeakconcentration
E.Therapeutic equivalence
Twodrugformulationsaretherapeuticallyequivalentiftheyare
pharmaceuticallyequivalent(thatis,theyhavethesamedosage
form,containthesameactiveingredient,andusethesameroute
ofadministration)withsimilarclinicalandsafetyprofiles.
Therefore, two drugs that are bioequivalent may not be therapeutically
equivalent.
47Presented by: Prof.Mirza Anwar
Baig

48. IV. DRUG DISTRIBUTION
•Drugdistributionistheprocessbywhichadrugreversiblyleaves
thebloodstreamandenterstheinterstitium(extracellularfluid)
andthetissues.
•FordrugsadministeredIV,absorptionisnotafactor,andthe
initialphase(fromimmediatelyafteradministrationthroughthe
rapidfallinconcentration)representsthedistributionphase,
duringwhichthedrugrapidlyleavesthecirculationandentersthe
tissues.
•Thedistributionofadrugfromtheplasmatotheinterstitium
dependsoncardiacoutputandlocalbloodflow,capillary
permeability,thetissuevolume,thedegreeofbindingofthedrug
toplasmaandtissueproteins,andtherelativelipophilicityofthe
drug.
48Presented by: Prof.Mirza Anwar
Baig

49. 49Presented by: Prof.Mirza Anwar
Baig

50. Factors affecting distribution:
A. Blood flow
B. Capillary permeability
C. Binding of drugs to plasma proteins and tissues
D. Lipophilicity
E. Volume of distribution
50Presented by: Prof.Mirza Anwar
Baig

51. A.Blood flow
1.Therateofbloodflowtothetissuecapillariesvarieswidely.
2.Forinstance,bloodflowtothe“vessel-richorgans”(brain,liver,
andkidney)isgreaterthanthattotheskeletalmuscles.Adipose
tissue,skin,andviscerahavestilllowerratesofbloodflow.
3.PropofolhasshortdurationofhypnosisproducedbyanIV
bolus.
4.Highbloodflow,togetherwithhighlipophilicityofpropofol,
permitsrapiddistributionintotheCNSandproducesanesthesia.
5.Asubsequentslowerdistributiontoskel-etalmuscleandadipose
tissuelowerstheplasmaconcentrationsothatthedrugdiffuses
outoftheCNS,downtheconcentrationgradient,and
consciousnessisregained.
51Presented by: Prof.Mirza Anwar
Baig

52. B.Capillary permeability
•Capillary permeabilityis determined by capillary structureand by the chemical
natureof the drug.
1.LIVERANDSPLEEN:
•Asignificantportionofthebasementmembraneisexposeddueto
large,discontinuouscapillariesthroughwhichlargeplasmaproteinscanpass.
2.BRAIN:
Thecapillarystructureiscontinuous,andtherearenoslitjunctions.
•Thesecloselyjux-taposedcellsformtightjunctionsthatconstitutetheblood–
brainbarrier.
•Forexample,aspecifictransportercarrieslevodopaintothebrain.Bycontrast,
lipid-solubledrugsreadilypenetratetheCNSbecausetheydissolveinthe
endothelialcellmembrane.
•IonizedorpolardrugsgenerallyfailtoentertheCNSbecausetheycannotpass
throughtheendothelialcellsthathavenoslitjunctions.
52Presented by: Prof.Mirza Anwar
Baig

53. C.Lipophilicity
1.The chemical nature of a drug strongly influences its ability to cross
cell membranes.
2.Lipophilicdrugsreadilymoveacrossmostbiologicmembranes.
3.Thesedrugsdissolveinthelipidmembranesandpenetratethe
entirecellsurface.
4.Themajorfactorinfluencingthedistributionoflipophilicdrugsis
bloodflowtothearea.
5.Incontrast,hydrophilicdrugsdonotreadilypenetratecell
membranesandmustpassthroughslitjunctions.
53Presented by: Prof.Mirza Anwar
Baig

54. D.Volume of distribution
Theapparentvolumeofdistribution,Vd,isdefinedasthe
fluidvolumethatisrequiredtocontaintheentiredruginthe
bodyatthesameconcentrationmeasuredintheplasma.
Vd=Amountofdrugintothebody
(C0)
Plasmaconcentrationattimezero(C0).
AlthoughVdhasnophysiologicorphysicalbasis,itcanbe
usefultocomparethedistributionofadrugwiththevolumes
ofthewatercompartmentsinthebody.
54Presented by: Prof.Mirza Anwar
Baig

55. 1. Distribution into the water compartments in
the body:
•Once a drug entersthe body, it has the potential to distribute into
any one of the three functionally distinct compartmentsof body
water or to become sequestered in a cellular site.
a. Plasma compartment:
If a drug has a high molecular weight or is extensively protein
bound, it is too large to passthrough the slit junctions of the
capillaries and, thus, is effectively trapped within the plasma
(vascular) compartment.
As a result, it has a low Vdthat approximates the plasma volume
or about 4 L in a 70-kg individual. Heparin shows this type of
distribution.
55Presented by: Prof.Mirza Anwar
Baig

56. b. Extracellular fluid:
•Drugwithlowmolecularweightbutishydrophilic,itcanpass
throughtheendothelialslitjunctionsofthecapillariesintothe
interstitialfluid.
•Hydrophilicdrugscannotmoveacrossthelipidmembranesofcells
toentertheintracellularfluid.
•Therefore,thesedrugsdistributeintoavolumethatisthesumofthe
plasmavolumeandtheinterstitialfluid,whichtogetherconstitute
theextracellularfluid(about20%ofbodyweightor14Lina70-kg
individual).
•Example:Aminoglycosideantibiotics
c.Total body water:
DrugwithLMWandislipophilic,itcanmoveintotheinterstitium
throughtheslitjunctionsandalsopassthroughthecellmembranes
intotheintracellularfluid.
Thesedrugsdistributeintoavolumeofabout60%ofbodyweight
orabout42Lina70-kgindividual.
56Presented by: Prof.Mirza Anwar
Baig

57. 2.Apparent volume of distribution:
1.Adrugrarelyassociatesexclusivelywithonlyoneofthewater
compartmentsofthebody.
2.Instead,thevastmajorityofdrugsdistributeintoseveral
compartments,oftenavidlybindingcellularcomponents,suchas
lipids(abundantinadipocytesandcellmembranes),proteins
(abundantinplasmaandcells),andnucleicacids(abundantincell
nuclei).
3.Therefore,thevolumeintowhichdrugsdistributeiscalledthe
apparentvolumeofdistribution(Vd).
4.Vdisausefulpharmacokineticparameterforcalculatingthe
loadingdoseofadrug.
57Presented by: Prof.Mirza Anwar
Baig

58. 3.Determination of Vd :
•The fact that drug clearance is usually
a first-order process allows calculation
of Vd . First order means that a
constant fraction of the drug is
eliminated per unit of time.
•This process can be most easily
analyzed by plotting the log of the
plasma drug concentration (Cp ) versus
time.
•The concentration of drug in the
plasma can be extrapolated back to
time zero (the time of IV bolus) on the
Y axis to determine C0 , which is the
concentration of drug that would have
been achieved if the distribution phase
had occurred instantly.
This allows calculation of Vd as
Vd= Dose/Co
58Presented by: Prof.Mirza Anwar
Baig

59. V. DRUG CLEARANCE THROUGH
METABOLISM
Once a drug enters the body, the process of elimination begins.
The three major routes of elimination are hepatic metabolism,
biliary elimination,and urinary elimination.
Together, these elimination processes decrease the plasma
concentration exponentially.
That is, a constant fraction of the drug present is eliminated in a
given unit of time.
Most drugs are eliminated according to first-order kinetics,
although some,such as aspirin in high doses, are eliminated
according to zero-order or nonlinear kinetics.
Metabolism leads to production of products with
increased polarity, which allows the drug to be eliminated.
59Presented by: Prof.Mirza Anwar
Baig

60. •Clearance(CL)estimatestheamountof
drugclearedfromthebodyperunitof
time.
•TotalCLisacompositeestimate
reflectingallmechanismsofdrug
eliminationandiscalculatedasfollows:
CL=0.693×Vd/t
1/2
60Presented by: Prof.Mirza Anwar
Baig

61. Kinetics of metabolism:
1.First-order kinetics:
The metabolic transformation of drugs is catalyzed by enzymes,
and most of the reactions obey Michaelis-Menten kinetics.
V max [ C ]
v = Rate of drug metabolism = ------------------------
K m + [ C ]
In most clinical situations, the concentration of the drug, [C], is
much lessthan the Michaelis constant, K m , and the Michaelis-
Menten equation reduces to
v = Rate of drug metabolism = V max [ C ]
K m
This means that a constant fraction of drug is metabolized per
unit of time (that is, with each half-life,the concentration
decreases by 50%). First-order kinetics is also referred to as linear
kinetics.
61Presented by: Prof.Mirza Anwar
Baig

62. 2.Zero-order kinetics:
•With a few drugs, such as aspirin, ethanol,and phenytoin, the doses
are very large. Therefore, [C] is much
greater than Km, and the velocity equation becomes
V max [ C ]
v = Rate of drug metabolism = [ C ] = V max
•The enzyme is saturatedby a high free drug concentration,
and the rate of metabolism remains constant over time. This is
called zero-order kinetics (also called nonlinear kinetics).
•A constant amount of drug is metabolized per unit of time.The rate
of elimination is constant and does not depend on the drug
concentration.
62Presented by: Prof.Mirza Anwar
Baig

63. B.Reactions of drug metabolism
The kidney cannot efficiently eliminate lipophilic drugsthat
readily cross cell membranes and are reabsorbed in the distal
convoluted tubules.
Therefore, lipid-soluble agents are first metabolized into more
polar (hydrophilic) substances in the liver via two general sets
of reactions, called phase I and phase II.
63Presented by: Prof.Mirza Anwar
Baig

64. 1.Phase I:
•PhaseIreactionsconvertlipophilicdrugsintomorepolar
moleculesbyintroducingorunmaskingapolarfunctionalgroup,such
as–OHor–NH2.
•PhaseIreactionsusuallyinvolvereduction,oxidation,orhydrolysis.
•PhaseImetabolismmayincrease,decrease,orhavenoeffecton
pharmacologicactivity.
•a.PhaseIreactionsutilizingtheP450system:
•Mostfrequentlyinvolvedreactionsindrugmetabolismarecatalyzedby
thecytochromeP450
•TheP450systemisimportantforthemetabolismofmanyendogenous
compounds(suchasste-roids,lipids)andforthebiotransformationof
exogenoussubstances(xenobiotics).
•CytochromeP450,designatedasCYP,isasuperfamilyofheme-
containingisozymesthatarelocatedinmostcells,butprimarilyinthe
liverandGItract.
64Presented by: Prof.Mirza Anwar
Baig

65. [1]Nomenclature:ThefamilynameisindicatedbytheArabic
numberthatfollowsCYP,andthecapitalletterdesignates
thesubfamily,forexample,CYP3A.Asecond
numberindicatesthespecificisozyme,asinCYP3A4.
[2]Specificity:
DifferentP450isoformspresent.
Havethecapacitytomodifyalargenumberofstructurally
diversesubstrates.
Anindividualdrugmaybeasubstrateformorethanone
isozyme.
FourisozymesareCYP3A4/5,CYP2D6,CYP2C8/9,andCYP1A2.
MostoftheCYP3A4arefoundinintestinalmucosa,accountingfor
first-passmetabolismofdrugssuchaschlorpromazineand
clonazepam.
65Presented by: Prof.Mirza Anwar
Baig

66. [3] Genetic variability:
P450 enzymes exhibit considerable genetic variabilityamong
individuals and racial groups.
Variations in P450 activity may alter drug efficacyand the
risk of adverse events.
CYP2D6, in particular, has been shown to exhibit genetic
polymorphism.
CYP2D6 mutations result in very low capacities to metabolize
substrates.
No benefitfrom the opioid analgesic codeine due to lack the
CYP2D6 enzyme that activates the drug.
Although CYP3A4 exhibits a greater than 10 fold variability
between individuals, no polymorphisms have been identified so far
for this P450 isozyme.
66Presented by: Prof.Mirza Anwar
Baig

67. [4] Inducers:
I.TheCYP450-dependentenzymesareanimportanttargetfor
pharmacokineticdruginteractionsthroughinducingtheCYP
isozymes.
II.Certaindrugs(phenobarbital,rifampin,andcarbamazepine)
increasingthesynthesisofoneormoreCYPisozymes.results
inlossofpharmacologicaleffectofdrugswhichare
metabolizedbytheseCYPisozymes.
III.Rifampinsignificantlydecreasestheplasmaconcentrationsof
HIVpro-teaseinhibitors,therebydiminishingtheirabilityto
suppressHIVreplication.
IV.St.John’swortisawidelyusedherbalproductandisapotent
CYP3A4inducer.
V.Manydruginteractionshavebeenreportedwithconcomitant
useofSt.John’swort.
67Presented by: Prof.Mirza Anwar
Baig

68. [5] Inhibitors:
Animportantsourceofdruginteractionsthatleadtoseriousadverse
events.
Inhibitionofdrugsmetabolismisthroughcompetitionforthesame
isozyme.
OmeprazoleisapotentinhibitorofthreeoftheCYPisozymes
responsibleforwarfarinmetabolism.
Ifthetwodrugsaretakentogether,plasmaconcentrationsofwarfarin
increase,whichleadstogreateranticoagulanteffectandincreasedriskof
bleeding.
MoreimportantCYPinhibitorsareerythromycin,ketoconazole,and
ritonavir,becausetheyeachinhibitseveralCYPisozymes.
GrapefruitjuiceinhibitsCYP3A4andleadstohigherlevelsand/orgreater
potentialfortoxiceffectswithdrugs,suchasnifedipine,clarithromycin,
andsimvastatin,thataremetabolizedbythissystem.
68Presented by: Prof.Mirza Anwar
Baig

69. b.Phase I reactions not involving the P450
system:
These include
Amine oxidation (catecholamines or histamine)
Alcohol dehydrogenation (ethanol oxidation)
Esterases (metabolism of aspirin in the liver)
Hydrolysis (procaine).
69Presented by: Prof.Mirza Anwar
Baig

70. 2.Phase II:(conjugation reactions)
•Polarmetaboliteofdrugscanbeexcretedbythekidneys.
•Lipophillicmetabolite(afterphaseImetabolism),subsequent
conjugationreactionwithanendogenoussubstrate,suchas
glucuronicacid,sulfuricacid,aceticacid,oranaminoacid,resultsin
polar,usuallymorewater-solublecompoundsthatareoften
therapeuticallyinactive.
•Anotableexceptionismorphine-6-glucuronide,whichismorepotent
thanmorphine.
•Glucuronidationisthemostcommonandthemostimportant
conjugationreaction.
•Drugsalreadypossessingan–OH,–NH2,or–COOHgroupmay
enterphaseIIdirectlyandbecomeconjugated
•Thehighlypolardrugconjugatesarethenexcretedbythekidneyor
inbile.
70Presented by: Prof.Mirza Anwar
Baig

71. VI. DRUG CLEARANCE BY THE KIDNEY
Polar drugsare eliminated easily from the body.
Number of routes are available for elimination, the most
important being elimination through the kidney into the urine.
Patients with renal dysfunction may be unable to excrete drugs
and are at risk for drug accumulation and adverse effects.
Elimination of drugs via the kidneys into urine involves the
processes
–Glomerular filtration,
–Active tubular secretion
–Passive tubular reabsorption.
71Presented by: Prof.Mirza Anwar
Baig

72. Summery Drug elimation:
72Presented by: Prof.Mirza Anwar
Baig

73. 1.Glomerularfiltration:
Freedrug(notboundtoalbumin)flowsthroughthecapillary
slitsintotheBowmanspaceaspartoftheglomerularfiltrate.
Theglomerularfiltrationrate(GFR)isnormallyabout125
mL/minbutmaydiminishsignificantlyinrenaldisease.
LipidsolubilityandpHdonotinfluencethepassageofdrugs
intotheglomerularfiltrate.
However,variationsinGFRandproteinbindingofdrugsdo
affectthisprocess.
73Presented by: Prof.Mirza Anwar
Baig

74. 2.Proximaltubularsecretion:
Drugsthatwerenottransferredintotheglomerularfiltrateleavethe
glomerulithroughefferentarterioles,(network)
Twoenergy-requiringactivetransportsystemstakepartinsecretionof
drugs:
a.Foranions(deprotonatedformsofweakacids)
b.Forcations(protonatedformsofweakbases).
Eachofthesetransportsystemsshowslowspecificityandcantransport
manycompounds.
Thus,competitionbetweendrugsforthesecarrierscanoccurwithineach
transportsystem.
74Presented by: Prof.Mirza Anwar
Baig

75. 3.Distal tubular reabsorption:
Asadrugmovestowardthedistalconvolutedtubule,itsconcentration
increasesandexceedsthatoftheperivascularspace.
Theunchargeddrugmaydiffuseoutofthenephriclumen,backintothe
systemiccirculation.
ManipulatingtheurinepHtoincreasethefractionofionizeddruginthe
lumenmaybedonetominimizetheamountofbackdiffusionandincrease
theclearanceofanundesirabledrug.
Asageneralrule,weakacidscanbeeliminatedbyalkalinizationofthe
urine,whereaseliminationofweakbasesmaybeincreasedbyacidificationof
theurine.Thisprocessiscalled“iontrapping.”
Forexample,apatientpresentingwithphenobarbital(weakacid)overdose
canbegivenbicarbonate,whichalkalinizestheurineandkeepsthedrug
ionized,therebydecreasingitsreabsorption.
75Presented by: Prof.Mirza Anwar
Baig

76. 4.Role of drug metabolism:
Mostdrugsarelipidsolubleand,withoutchemical
modification,woulddiffusefromthetubularlumento
perivascularspace(why)duetoconcentrationgradient
betweenthedrugconcentrationinthefiltrateandperivascular
space.
Tominimizethisreabsorption,drugsaremodifiedprimarilyin
theliverintomorepolarsubstancesviaphaseIand
phaseIIreactions.
Thepolarorionizedconjugatesareunabletobackdiffuseout
ofthekidneylumen.
76Presented by: Prof.Mirza Anwar
Baig

77. Summery Drug elimation:
77Presented by: Prof.Mirza Anwar
Baig

78. VII. CLEARANCE BY OTHER ROUTES
Drugclearancemayalsooccurviatheintestines,bile,lungs,andbreast,milketc.
Drugsthatarenotabsorbedafteroraladministrationordrugsthataresecreted
directlyintotheintestinesorintobileareeliminatedinthefeces.
Thelungsareprimarilyinvolvedintheeliminationofanestheticgases(for
example,isoflurane).
Eliminationofdrugsinbreastmilkmayexposethebreast-feedinginfantto
medicationsand/ormetabolitesbeingtakenbythemotherandisapotential
sourceofundesirablesideeffectstotheinfant.
Excretionofmostdrugsintosweat,saliva,tears,hair,andskinoccursonlytoa
smallextent.
Totalbodyclearanceanddrughalf-lifeareimportantmeasuresofdrugclearance
thatareusedtooptimizedrugtherapyandminimizetoxicity.
78Presented by: Prof.Mirza Anwar
Baig

79. A.Total body clearance:
Thetotalbody(systemic)clearance,CLtotal,isthesumofall
clearancesfromthedrug-metabolizinganddrug-eliminating
organs.
Thekidneyisoftenthemajororganofelimination.Theliver
alsocontributestodrugclearancethroughmetabolismand/or
excretionintothebile.
Totalclearanceiscalculatedusingthefollowingequation:
CLtotal=CLhepatic+CLrenal+CLpulmonary+CLother
whereCLhepatic+CLrenalaretypicallythemostimportant.
79Presented by: Prof.Mirza Anwar
Baig

80. B.Clinical situations resulting in changes in drug half-life
•Adjustment in dosage is required when a patient has an abnormality.
Increase in drug half-life include in case of
1) diminished renal or hepatic blood flow
2) decreased ability to eliminate drug from plasma
3) decreased metabolism,
These patients may require a decrease in dosage or less frequent dosing intervals.
In contrast, the half-life of a drug may be
1) decreased by increased hepatic blood flow
2)decreased protein binding, or increased metabolism.
This may necessitate higher doses or more frequent dosing intervals.
80Presented by: Prof.Mirza Anwar
Baig

81. FACTORS MODIFYING
DRUG ACTION
81Presented by: Prof.Mirza Anwar
Baig

82. Factors:
1. Body weight
2. Age
3. Sex
4. Species and race
5. Genetics
6. Route of administration
7. Environmental factors and time of administration
8. Psychological factor
9. Pathological states
82Presented by: Prof.Mirza Anwar
Baig

83. Introduction:
Variation in response to the same dose of a drug between different
patients and even in the same patient on different occasions was
observed.
Categories of differences among individuals are responsible for
the variations in drug response:
(1)Individuals differ in pharmacokinetic handling of drugs:
(2) Variations in number or state of receptors,coupling proteins or other
components of response effectuation.
(3) Variations in neurogenic/hormonal tone or concentrations of specific
constituents, e.g. atropine tachycardia depends on vagaltone,
propranololbradycardiadepends on sympathetic tone
83Presented by: Prof.Mirza Anwar
Baig

84. The factors modify drug action either:
a)Quantitatively:
The plasma concentration of the drug is increased or decreased. Most
of the factors introduce this type of change and can be dealt with by
adjustment of drug dosage.
b) Qualitatively:
The type of response is altered, e.g. drug allergy or idiosyncrasy. This
is less common but often precludes further use of that drug in the
affected patient.
84Presented by: Prof.Mirza Anwar
Baig

85. Factors affecting dose response:
Fall in two categories
1. Genetic 2. Non genetic
Provide guidance for the selection of appropriate drug and
dose for an individual patient.
However, final adjustments have to be made by observing the
response in a given patient on a given occasion.
85Presented by: Prof.Mirza Anwar
Baig

86. Factors modifying drug action:
1. Body size:
It influences the concentration of the drug attained at the site of action.
The average adult dose refers to individuals of medium built.
For exceptionally obese or lean individuals and for children dose may be calculated
on body weight (BW) basis:
It has been argued that body surface area (BSA) provides a more accurate basis for
dose calculation, because total body water, extracellular fluid volume and
metabolic activity are better paralleled by BSA.
86Presented by: Prof.Mirza Anwar
Baig

87. 2. Age:
Infantsandchildrenhaveimportantphysiologicaldifferencesfromadults.
Thenewbornhaslowg.f.r.andtubulartransportisimmature.
Thet
1/2ofdrugsexcretedbyglomerularfiltration(gentamicin)andtubular
secretion(penicillin)isprolongedby3to5times.
Glomerularfiltrationreachesadultratesby5monthofageandtubular
secretiontakesabout7monthstomature.
Hepaticdrugmetabolizingsystemisinadequateinnewborns-
chloramphenicolcanproducegraybabysyndrorne.
Blood-brainbarrierismorepermeable-drugsattainhigherconcentrationin
theCNS(accumulationofunconjugatedbilirubincauseskernicterus).
Drugabsorptjonmayalsobealteredininfantsbecauseoflowergastric
acidityandslowerintestinaltransit.
Transdermalabsorption,isfasterbecausetheirskinisthinandmore
permeable.
87Presented by: Prof.Mirza Anwar
Baig

88. Afterthefirstyearoflife,drugmetabolismisoftenfasterthan
inadults,e.g.theophylline,phenytoin,carbamazepinet
1/2is
shorterinchildren.
Soliddosageformsandaerosolinhalationsaredifficultto
administertoyoungchildren.
Childrenaregrowingandaresusceptibletospecialadverse
effectsofdrugseg:suppressionofgrowthcanoccurwith
corticosteroiods.
Intheelderly,renalfunctionprogressivelydeclines(intact
nephronloss)sothatis-75%at50yearsand-50%at75year'
comparedtoyoungadults.Drugdoseshastobereduced
88Presented by: Prof.Mirza Anwar
Baig

89. 3. Sex
a.Females have smaller body sizeand require doses that are on the lower side
of the range.
b.Subjective effects of drugs may differ in females because of their mental
makeup .
c.Maintenance treatment of heart failure with digoxinis reported to be
associated with higher mortality among women than among men.
d.A number of antihypertensives( clonidine, methyldopa, Beta-blockers,
diuretics) interfere with sexual function in males but not in females .
e.Gynaecomastiais a side effect (of ketoconazole, metoclopramide,
chlorpromazine, digitalis) that can occur only in men.
f.Ketoconazole causes loss of libidoin men but not in women.
g.Androgens are unacceptable to women and estrogens to men. In women
consideration must also be given to menstruation, pregnancy and lactation.
89Presented by: Prof.Mirza Anwar
Baig

90. Drugsgivenduringpregnancycanaffectthefoetus.
Therearemarkedandprogressivephysiologicalchangesduringpregnancy,
especiallyinthethirdtrimester,whichcanalterdrugdisposition.
(i)Gastrointestinalmotilityisreduced->delayedabsorptionoforally
administereddrug.
(ii)Plasmaandextracellularfluidvolumeexpands-volumeofdrugdistributionmay
increase.
(iii)Whileplasmaalbuminlevelfalls,-theunboundfractionofacidicdrugs
increasesbutthatofbasicdrugsdecreases.
(iv)Renalbloodflowincreasesmarkedlypolardrugsareeliminatedfaster.
(v)Hepaticmicrosomalenzymesundergoinduction-manydrugsaremetabolized
faster.
Thus,theoveralleffectondrugdispositioniscomplexandoftendifficulttopredict.
90Presented by: Prof.Mirza Anwar
Baig

91. 4. Species and race
•Rabbitsare resistant to atropine.
•Rats and mice are resistant to digitalis and rat is more sensitive to curare than
cat.
•These differences are important while extrapolating results from experimental
animals to man.
•Blacksrequire higher and Mongolsrequire lower concentrations of atropine
and ephedrine to dilate their pupil.
•Beta-blockers are less effective as antihypertensive in AfroCaribbeans.
•Indians tolerate thiacetazone better than whites.
91Presented by: Prof.Mirza Anwar
Baig

92. 5. Genetics
The dose of a drug to produce the same effect may vary by 4--6 fold among
different individuals.
All key determinants of drug response, viz. transporters, metabolizing
enzymes, ion channels, receptors with their couplers and effectors are
controlled genetically.
The study of genetic basis for variability in drug response is called
'Pharmacogenetics'.
As the genomic technology has advanced, gene libraries and huge data bases
(like 'pharmacogeneticsand pharmacogenomicsknowledge base', 'Human
genome variation database', etc.) have been created aiming at improving
precision in drug therapy.
92Presented by: Prof.Mirza Anwar
Baig

93. 6. Route of administration
•It governs the speed and intensity of duration of response.
•Parenteral administrationis often resorted to for more rapid, more
pronounce and more predictable drug action.
•A drug may have entirely different uses through different routes,
e.g. magnesium sulfate given orally cause: purgation, applied on
sprained joints-decreases swelling, intravenously it produces
depression and hypotension.
93Presented by: Prof.Mirza Anwar
Baig

94. 7. Environmental factors and time of administration
Exposure to insecticides, carcinogens,tobaccosmoke and consumption of
charcoil,broiledmeat are well known to induce drug metabolism.
8. Psychological factor:
Efficacy of a drug can be affected by patient's beliefs, attitudes and
expectations.
This is particularly applicable to centrally acting drugs, e.g. a nervous and
anxious patient requires more general anaesthetic; Alcohol generally
impairs performance.
Punishment (which induces anxiety)is introduced, it may actually improve
performance.
94Presented by: Prof.Mirza Anwar
Baig

95. References:
1.Rang H. P., Dale M. M., Ritter J. M., Flower R. J., Rang and Dale‘s
Pharmacology,.Churchil Livingstone Elsevier
2.Katzung B. G., Masters S. B., Trevor A. J., Basic and clinical pharmacology, Tata
Mc Graw-Hill
3.Goodman and Gilman‘s, The Pharmacological Basis of Therapeutics
4.Marry Anne K. K., Lloyd Yee Y., Brian K. A., Robbin L.C., Joseph G. B., Wayne A.
K.,Bradley R.W., Applied Therapeutics, The Clinical use of Drugs, The Point
Lippincott Williams & Wilkins
5.Mycek M.J, Gelnet S.B and Perper M.M. Lippincott‘s Illustrated Reviews-
Pharmacology
6.K.D.Tripathi. Essentials of Medical Pharmacology, JAYPEE Brothers Medical
Publishers (P) Ltd, New Delhi.
Presented by: Prof.Mirza Anwar
Baig
95

96. Thank You
96Presented by: Prof.Mirza Anwar
Baig